Imaging of coronary atherosclerosis and vulnerable plaque Velzen, J.E. van

Imaging of coronary atherosclerosis and vulnerable plaque

Velzen, J.E. van

Citation

Velzen, J. E. van. (2012, February 16). Imaging of coronary atherosclerosis and vulnerable plaque. Retrieved from https://hdl.handle.net/1887/18495

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CHAPTER 5

Diagnostic Performance of Non- Invasive Multidetector Computed Tomography Coronary Angiography to Detect Coronary Artery Disease using Different Endpoints;

Detection of Significant

Stenosis versus Detection of Atherosclerosis

Joëlla E. van Velzen, Joanne D. Schuijf, Fleur R. de Graaf, Eric Boersma, Gabija Pundziute, Fabrizio Spano ,

, Mark J. Boogers, Martin J. Schalij, Lucia J.

Kroft, Albert de Roos, J. Wouter Jukema, Ernst E. van der Wall, Jeroen J. Bax

Eur Heart J. 2011 Mar;32(5):637-4

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ABSTRACT

Background: The positive predictive value of multidetector computed tomography angiography (CTA) for detecting signifi cant stenosis remains limited. Possibly CTA may be more accurate in the evaluation of atherosclerosis rather than in the evaluation of stenosis severity. However, a comprehensive assessment of the diagnostic performance of CTA in comparison to both conventional coronary angiography (CCA) and intravascular ultra- sound (IVUS) is lacking. Therefore, the aim of the study was to systematically investigate the diagnostic performance of CTA for 2 endpoints, namely detecting signifi cant stenosis (using CCA as the reference standard) versus detecting the presence of atherosclerosis (using IVUS as reference of standard).

Methods: A total of 100 patients underwent CTA followed by both CCA and IVUS. Only those segments in which IVUS imaging was performed were included for CTA and QCA analysis. On CTA, each segment was evaluated for signifi cant stenosis (defi ned as ≥50%

luminal narrowing), on CCA signifi cant stenosis was defi ned as a stenosis ≥50%. Secondly, on CTA, each segment was evaluated for atherosclerotic plaque, atherosclerosis on IVUS was defi ned as a plaque burden of ≥40% on cross-sectional area.

Results: CTA correctly ruled out signifi cant stenosis in 53 of 53 (100%) patients. However, 9 patients (19%) were incorrectly diagnosed as having signifi cant lesions on CTA resulting in sensitivity, specifi city, positive and negative predictive values of 100%, 85%, 81% and 100%. CTA correctly ruled out the presence of atherosclerosis in 7 patients (100%) and correctly identifi ed the presence of atherosclerosis in 93 patients (100%). No patients were incorrectly classifi ed, resulting in sensitivity, specifi city, positive and negative predic- tive values of 100%.

Conclusion: The present study is the fi rst to confi rm using both CCA and IVUS that the

diagnostic performance of CTA is superior in the evaluation of the presence or the absence

of atherosclerosis when compared with the evaluation of signifi cant stenosis.

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INTRODUCTION

With the introduction of multidetector computed tomography angiography (CTA) technol- ogy, non-invasive imaging of coronary anatomy has become possible. The technique has developed rapidly and is increasingly used for the evaluation of coronary artery disease (CAD), although the precise role of CTA in the assessment of CAD has not been adequately defi ned yet. On the basis of the high specifi city and the high negative predictive value, CTA has an excellent ability of ruling out signifi cant CAD.

However, relatively low positive predictive values have been reported and frequently the presence of a signifi cant stenosis that is observed on CTA is not confi rmed on con- ventional coronary angiography (CCA).

This discrepancy between CTA and CCA has been attributed to the inferior spatial and temporal resolution of CTA when compared with CCA and at present it seems that the technique remains inferior to CCA. However, one could also question the use of CCA as a reference standard. In contrast to the lumino- graphic approach of CCA, CTA is a cross-sectional or tomographic imaging technique. As a result, CTA allows direct visualization of the coronary vessel wall and thus the presence of coronary atherosclerosis. It is anticipated that precisely this information will become increasingly important in the evaluation and subsequent management of patients with CAD.

Possibly the true strength of coronary CTA may therefore lie in the evaluation of atherosclerosis rather than evaluation of signifi cant stenosis.

Thus far diagnostic accuracy studies have only evaluated the performance of CTA using invasive CCA as the standard of reference.

Nonetheless, it is conceivable that CTA may perform better when compared with IVUS (using atherosclerosis as endpoint) than when compared with CCA (using signifi cant stenosis as endpoint). However, thus far no studies have addressed this issue by combing these endpoints in a large cohort of patients. Such a comprehensive evaluation would provide valuable information to further understand how CTA should be used in clinical practice. Therefore, the purpose of this study was to provide a systematic evaluation concerning both the diagnostic accuracy for the detection of signifi cant stenosis (using CCA as the reference standard) and the diagnostic accuracy for the detection of atherosclerosis (using IVUS as the reference standard) in a large cohort of patients.

METHODS

Patients and study protocol

The study group consisted of 106 patients without known CAD who were clinically referred

for coronary CTA because of chest pain or elevated risk profi le. On the basis of imaging

results and clinical presentation patients were referred for CCA in combination with IVUS of

1 - 3 vessels and enrolled in the present study. Contra-indications for CTA were 1) (supra)

ventricular arrhythmias, 2) renal insuffi ciency (glomerular fi ltration rate <30 ml/min), 3)

known allergy to iodine contrast material, 4) severe claustrophobia, 5) pregnancy. Exclusion

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92

criteria for IVUS were severe vessel tortuousness, severe stenosis or vessel occlusion. In each patient, the presence of CAD risk factors including diabetes, systemic hypertension, hypercholesterolemia, positive family history, smoking and obesity, were recorded. Patients were classifi ed as having a low, intermediate or high pre-test likelihood of CAD using the method described by Diamond and Forrester.

The study protocol was approved by the institutional ethics committee, and informed consent was obtained in all patients.

Multidetector computed tomography angiography Data acquisition

Beta-blocking medication (metoprolol 50 or 100 mg, single oral dose, 1 hour prior to examination) was administered in case of a heart rate ≥65 beats/min and in the absence of contra-indications. CTA was performed using either a 64-detector row helical scanner (Aquilion 64, Toshiba Medical Systems, Toshiba Medical Systems, Otawara, Japan) or a 320-detector row volumetric scanner (Aquilion ONE, Toshiba Medical Systems, Otawara, Japan). For the 64-row contrast-enhanced scan, collimation was 64 x 0.5 mm, tube voltage 100 - 135 kV and tube current 250 - 350 mA, depending on body posture. Non-ionic contrast material (Iomeron 400, Bracco, Milan, Italy) was administered with an amount of 80 - 110 ml followed by a saline fl ush with a fl ow rate of 5 ml/s. Data acquisition was performed during an inspiratory breath hold of ~ 8 - 10 seconds. Datasets were reconstructed from the retrospectively gated raw data, the best phase was reconstructed with an interval of 0.3 mm. Using a single test slice reconstructed throughout the vari- ous phases of the heart cycle, other suitable R-R intervals were examined for additional reconstructions.

For the 320-row contrast-enhanced scan the heart was imaged in a single heartbeat, using prospective triggering with exposure interval depending on the heart rate. Scan parameters were: 350 ms gantry rotation time, 100 - 135 kV tube voltage, and a tube current of 400 - 580 mA, depending on body mass index (BMI). In total, 60 - 90 ml contrast material (Iomeron 400) was administered with a fl ow rate of 5 - 6 ml/s followed by a saline fl ush. Automatic peak enhancement detection in the left ventricle was used for timing of the bolus using a threshold of +180 Hounsfi eld Units. Data acquisition was performed during an inspiratory breath hold of ~ 4 - 6 seconds. Subsequently, data sets were reconstructed and transferred to a remote workstation as previously described.

Data analysis

CTA scans were evaluated using dedicated software (Vitrea 2.0 or Vitrea FX 1.0, Vital

images, Minnetonka, MN, USA). CTA examinations were evaluated by two experienced

readers (blinded to CCA and IVUS results). Disagreement between readers was resolved

in consensus. Three-dimensional rendered reconstructions were used to obtain general

information on the anatomy of the coronary arteries. Coronary arteries were subsequently

divided into 17 segments according to a modifi ed American Heart Association classifi ca-

tion.

First, to evaluate the presence of signifi cant stenosis, each segment was evaluated

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for the presence of luminal narrowing using axial and/or orthogonal images and curved multiplanar reconstructions. Atherosclerotic lesions were deemed signifi cant stenosis if resulting in ≥50% luminal narrowing. Lesions below this threshold were considered to be non-signifi cant. Second, to evaluate the presence of atherosclerosis, each segment was evaluated for the presence of any atherosclerotic plaque on axial and/or orthogonal images and curved multiplanar reconstructions. Structures >1 mm

within and/or adja- cent to the coronary artery lumen, which could be clearly distinguished from the vessel lumen, were defi ned as atherosclerotic plaque.

Conventional and quantitative coronary angiography (QCA)

CCA was performed according to standard protocols. QCA analysis was performed on a segmental basis by an observer unaware of CTA and IVUS fi ndings with the use of QCA-CMS version 6.0 (Medis, Leiden, The Netherlands). QCA was performed only in those segments with plaque. Plaque on invasive CCA was defi ned as any evidence of luminal narrowing of any degree, clinically signifi cant or not, or evidence of calcifi cation on angiogram before or after contrast injection.

The tip of the catheter was used for cali- bration and for each segment examined both with CTA and IVUS, the reference diameter and minimum luminal diameter were measured and percentage diameter stenosis was reported. Measurements were performed on at least two orthogonal projections and the highest percentage diameter stenosis was used for further analysis. Signifi cant stenosis was defi ned as ≥50% luminal narrowing.

Intravascular ultrasound Image acquisition

IVUS examinations were acquired during CCA in 219 of the 300 available vessels with the use of a dedicated IVUS-console (Volcano Corporation, Rancho Cordova, CA, USA).

IVUS was performed with a 20 MHz, 2.9 F phased-array IVUS catheter (Eagle Eye, Volcano Corporation, Rancho Cordova, CA, USA), which was introduced distally in the coronary artery under fl uoroscopic guidance, after administration of nitrates locally. A motorized automated pullback with a continuous speed of 0.5 mm/s was used until the catheter reached the guiding catheter. Cine runs before and after contrast injections were per- formed to confi rm the position of the IVUS catheter. Images were stored on CD-ROM or DVD for offl ine analysis.

Image analysis

IVUS analysis was performed by two blinded observers. Lumen and external elastic

membrane (EEM) contours were manually traced to determine lumen area and EEM area

(QCU-CMS, version 4.5, Leiden, the Netherlands). In each segment, the site with minimum

lumen area (mm

) was identifi ed. Additionally, cross-sectional area measurements of EEM,

lumen area and percentage plaque burden (plaque and media area / EEM area multiplied

by 100) were performed. The measurements were performed in accordance with the

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IVUS guidelines of the American College of Cardiology.

The presence of visually evident atherosclerosis on IVUS was defi ned as a plaque burden of ≥40% cross-sectional area on at least three consecutive frames.

An example of an IVUS cross-sectional image with a plaque burden of ≥40% is demonstrated in Figure 1.

Statistical analysis

Only those segments in which IVUS imaging was performed were included for CTA and QCA analysis. First, the diagnostic accuracy (sensitivity, specifi city, positive and negative predictive values including 95% confi dence intervals) of CTA for the detection of signifi - cant stenosis (luminal narrowing ≥50% on CCA) was calculated on segmental, vessel and patient basis. CCA was the standard of reference for detection of signifi cant stenosis and a segment, vessel or patient was classifi ed as true positive if a signifi cant stenosis was identi- fi ed correctly by CTA. Second, the diagnostic accuracy (sensitivity, specifi city, positive and negative predictive values including 95% confi dence intervals) of CTA for the detection of atherosclerosis (plaque burden ≥40% on cross-sectional area on IVUS) was calculated on segmental, vessel and patient basis. IVUS was the standard of reference for the detection of atherosclerosis and a segment, vessel, or patient was classifi ed as true positive if the presence of atherosclerosis was identifi ed correctly by CTA. In the analysis on a vessel basis, the left main was considered part of the left anterior descending artery (LAD) and the intermediate branch was considered part of the left circumfl ex artery (LCx). Initially, the diagnostic accuracy was determined excluding segments of non-diagnostic image quality. In a subsequent analysis, non-diagnostic segments were included in the analysis and were considered positive for stenosis and atherosclerosis. Differences between the diagnostic accuracy for the two different endpoints were considered signifi cant at the

A B

Figure 1. Example of intravascular ultrasound IVUS) cross-sectional image without (A) and with

border detection (B). Cross-sectional image of coronary atherosclerosis with vessel border (green)

and lumen (red) border tracing demonstrated in panel B. The IVUS image corresponds to a plaque

burden of 41%.

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95

0.05 level if 95% confi dence intervals did not overlap. Continuous values were expressed as means (± standard deviation) if normally distributed and compared with the two-tailed t-test for independent samples. If not normally distributed, values were expressed as medians and interquartile range (IQR) and compared with the 2-tailed Mann-Whitney test. A p-value of <0.05 was considered statistically signifi cant.

To account for possible clustering of coronary artery segments and vessels within patients, the generalized estimating equation (GEE) method was applied for stenosis and atherosclerosis evaluation. When compared to QCA, CTA was scored as signifi cant steno- sis present (luminal narrowing ≥50% and non-diagnostic segments) or absent (luminal narrowing <50%). When compared to IVUS, CTA was scored as atherosclerosis present (including non-diagnostic segments) or absent. First, regular binary logistic regression analysis was performed to evaluate the predictive value of CTA for the presence of sig- nifi cant stenosis on QCA and the predictive value of CTA for presence of atherosclerosis on IVUS. Second, to adjust for clustering of segments within patient, GEE analyses were

performed with proc GENMOD with a binominal distribution for the outcome variable, the link function specifi ed as logit, and patients as separate subjects. In both analyses the parameters of estimation and the standard error were virtually identical, suggesting that Table 1. Patient characteristics of the study.

Gender (male/female) 64/36

Age (years) 57 ± 11

Risk factors for CAD (%)

Diabetes 29 (29%)

Hypertension 60 (60%)

Hypercholesterolaemia 62 (62%)

Positive family history 44 (44%)

Current smoking 47 (47%)

Obese (BMI ≥30 kg/m

) 21 (21%)

Symptoms (%)

Typical angina 27 (27%)

Atypical angina 27 (27%)

Non-anginal chest pain 46 (46%)

Pre-test likelihood (%)

Low 24 (24%)

Intermediate 57 (57%)

High 19 (19%)

Prevalence segments with ≥50% luminal narrowing on QCA 58 (11%) Prevalence segments with ≥40% plaque burden on IVUS 329 (65%)

BMI; body mass index, QCA; quantitative coronary angiography; IVUS, intravascular ultrasound

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no clustering within patients was present. Statistical analysis was performed using SPSS 14.0 software (SPSS Inc., Chicago. Illinois, USA).

RESULTS

Patient characteristics

In the study population of 106 patients, overall image quality on CTA was reduced in 6 patients (6%). Reasons for reduced image quality were the presence of motion artifacts, increased noise due to a high BMI, elevated heart rate and breathing. Accordingly, these patients were not included in the analysis. Patient characteristics of the remaining 100 patients are presented in Table 1. The average age of the patient group was 57 ± 11 years and 64 were male (64%). The majority of patients (57%) had an intermediate pre-test likelihood for CAD. The average interval between CTA and CCA including IVUS was 61

± 73 days. In total, in 528 segments both CTA and invasive data (CCA and IVUS analysis) were available (right coronary artery = 72, left anterior descending coronary artery = 87, left circumfl ex coronary artery = 60). Image quality was insuffi cient in 18 segments (3%) because of small vessel size (n= 8), a high BMI resulting in increased noise (n=3) and motion artifacts (n=7) and these segments were excluded. For this study estimated mean radiation dose for the 320-row CTA was 3.2 ± 1.1 mSv if scanned full dose at 75% of R-R interval. In patients who were scanned full dose at 65-85% of R-R interval, estimated mean radiation dose was 7.1 ± 1.7 mSv. For the 64-row CTA the estimated mean radiation dose was 18.1 ± 5.9 mSv in patients scanned for the full R-R interval, retrospectively gated.

Diagnostic accuracy of CTA for the detection of signifi cant stenosis

The diagnostic accuracy of CTA (with 95% confi dence intervals) for the detection of

signifi cant stenosis on a segment, vessel and patient basis excluding and including non-

diagnostic segments is presented in Table 2. When excluding non-diagnostic segments,

the presence of stenosis was correctly ruled out by CTA in 435 of 452 segments, without

signifi cant stenosis on CCA, whereas 57 of the 58 segments were correctly classifi ed as

having a signifi cant stenosis. However, CTA overestimated a total of 17 lesions deemed

non-signifi cant on CCA and underestimated 1 lesion which was signifi cant on CCA. On a

segmental basis, this resulted in a sensitivity and specifi city of respectively 98% and 96%,

and positive and negative predictive values of 77% and 99%, respectively. On a vessel

basis, a total of 47 vessels out of the 219 vessels were identifi ed as signifi cant stenosis on

CCA. CTA correctly identifi ed all the 47 vessels as signifi cant (100%). In the remaining 172

vessels, CTA correctly identifi ed 158 vessels as non-signifi cant (92%). However, 14 vessels

were overestimated as signifi cant CAD by CTA. On a vessel basis, this resulted in a sensi-

tivity and specifi city of respectively 100% and 92%, and positive and negative predictive

values of 77% and 100%, respectively. On a patient basis, CTA correctly ruled out signifi -

cant CAD in 53 of 62 (85%) patients without signifi cant stenosis on CCA. Additionally, CTA

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correctly identifi ed 38 of 38 patients (100%) with one or more signifi cant lesions. However, nine patients (19%) were incorrectly classifi ed as having signifi cant lesions on CTA.

Diagnostic accuracy of CTA for the detection of atherosclerosis

The diagnostic accuracy of CTA (with 95% confi dence intervals) for the detection of athero- sclerosis on a segment, vessel and patient basis, excluding and including non-diagnostic segments is presented in Table 3. In the 510 evaluated segments, median minimal lumen area was 6.7 mm

(IQR 4.5 - 10.1 mm

), median EEM area was 14.0 mm

(IQR 10.0 - 20.0 mm

) and median percentage plaque burden was 42% (IQR 34 - 50%). When excluding non-diagnostic segments, 329 segments with atherosclerosis were detected by IVUS, of which 326 were correctly identifi ed by CTA (sensitivity 99%). CTA incorrectly classifi ed three segments as without atherosclerosis. In addition, of the 181 segments considered without atherosclerosis by IVUS, atherosclerosis was correctly excluded in 179 segments by CTA (specifi city 99%) and two segments were incorrectly classifi ed as positive for atherosclerosis. On a vessel basis, 172 vessels out of 173 vessels which were deemed positive for atherosclerosis by IVUS were correctly identifi ed by CTA (99%). Moreover, CTA correctly ruled out presence of atherosclerosis in the 45 out of 46 vessels deemed nega- tive for atherosclerosis by IVUS. Thus, CTA overestimated only one vessel as positive and underestimated one vessel as negative for atherosclerosis. On a vessel basis, this resulted in a sensitivity and specifi city of respectively, 99% and 98% and a positive and negative predictive value of 99% and 98%, respectively. On a patient basis CTA correctly ruled out the presence of atherosclerosis in 7 patients (100%), and correctly identifi ed the presence Table 2. Diagnostic accuracy for the detection of signifi cant stenosis, excluding and including non- diagnostic segments.

Segmental Analysis Vessel Analysis Patient Analysis Excluding non-diagnostic segments

Sensitivity 57/58 (98%, 95%-100%) 47/47 (100%) 38/38 (100%) Specifi city 435/452 (96%, 94%-97%) 158/172 (92%, 88%-96%) 53/62 (85%, 78%-93%) PPV 57/74 (77%, 69%-85%) 47/61 (77%, 67%-88%) 38/47 (81%, 71%-90%) NPV 435/436 (99.7%, 99%-100%) 158/158 (100%) 53/53 (100%)

Diagnostic Accuracy 492/510 (96%, 95%-98%) 205/219 (94%, 90%-97%) 91/100 (92%, 86%-96%) Including non-diagnostic segments

Sensitivity 60/61 (98%, 95%-100%) 47/47 (100%) 38/38 (100%) Specifi city 435/467 (93%, 91%-95%) 149/172 (87%, 82%-92%) 53/62 (85%, 78%-93%) PPV 60/92 (65%, 55%-75%) 47/70 (67%, 56%-78%) 38/47 (81%, 71%-90%) NPV 435/436 (99.7%, 99%-100%) 149/149 (100%) 53/53 (100%)

Diagnostic Accuracy 495/528 (94%, 92%-96%) 196/219 (90%, 85%-94%) 91/100 (92%, 86%-96%) Accuracy and 95% confi dence intervals of CTA to detect signifi cant stenosis using CCA as the standard of reference [segmental (n=510), vessel (n=219) and patient (n=100) analysis], excluding and including non-diagnostic segments.

PPV; positive predictive value, NPV; negative predictive value.

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Table 3. Diagnostic accuracy for the detection of atherosclerosis, excluding and including non- diagnostic segments.

Segmental Analysis Vessel Analysis Patient Analysis Excluding non-diagnostic segments

Sensitivity 326/329 (99%, 98%-100%) 172/173 (99%, 98%-100%) 93/93 (100%) Specifi city 179/181 (99%, 97%-100%) 45/46 (98%, 94%-100%) 7/7 (100%) PPV 326/328 (99%, 99%-100%) 172/173 (99%, 98%-100%) 93/93 (100%) NPV 179/182 (98%, 97%-100%) 45/46 (98%, 94%-100%) 7/7 (100%) Diagnostic Accuracy 505/510 (99%, 98%-99.8%) 217/219 (99%, 98%-100%) 100/100 (100%) Including non-diagnostic segments

Sensitivity 343/346 (99%, 98%-100%) 172/173 (99%, 98%-100%) 93/93 (100%) Specifi city 179/182 (98%, 97%-100%) 45/46 (98%, 94%-100%) 7/7 (100%) PPV 343/346 (99%, 98%-100%) 172/173 (99%, 98%-100%) 93/93 (100%) NPV 179/182 (98% (97%-100%) 45/46 (98 %, 94%-100%) 7/7 (100%) Diagnostic Accuracy 522/528 (99%, (98%-99.7%) 217/219 (98%, 99%-100%) 100/100 (100%) Accuracy and 95% confi dence intervals of CTA for the detection of atherosclerosis, with IVUS as the standard of reference [segmental (n=510), vessel (n=219) and patient (n=100) analysis], excluding and including non-diagnostic segments.

PPV; positive predictive value, NPV; negative predictive value.

p<0.001

p=0.484

Figure 2A. Difference in percentage luminal narrowing between true and false positives for detection of signifi cant stenosis on multidetector computed tomography angiography (CTA). Box plot graph illustrating the difference in percentage luminal narrowing on conventional coronary angiography (CCA) between true positive (median = 61%) and false positive (median = 39%) lesions for signifi cant stenosis on CTA.

Figure 2B. Difference in percentage plaque burden between true and false positives for signifi cant stenosis on multidetector computed tomography angiography (CTA).

Boxplot illustrating the difference in percentage plaque burden on intravascular ultrasound (IVUS) between lesions true positive (median

= 56%) and false positive (median = 56%) for

signifi cant stenosis on CTA.

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of atherosclerosis in 93 patients (100%) resulting in sensitivity, specifi city, positive and negative predictive values of 100%.

Quantitative analysis of CCA and IVUS characteristics of lesions with correct and incorrect diagnosis of signifi cant stenosis on CTA

To explore the differences between lesions correctly identifi ed as a signifi cant stenosis by CTA (true positives) and lesions incorrectly identifi ed as signifi cant lesions by CTA (false positives), CCA, and IVUS characteristics were compared. As demonstrated in Figure 2A, percentage luminal narrowing on CCA was signifi cantly higher in true positives when compared with false positives (61% (IQR 57 - 70%) versus 39% (IQR 28 - 43%) p<0.001).

A B C

E D

Figure 3. Case example of a 65 year old male with extensive coronary artery disease (CAD)

as demonstrated by 320-row multidetector computed tomography angiography (CTA) and

intravascular ultrasound (IVUS) while conventional coronary angiography (CCA) showed no

signifi cant CAD. (A) 3D volume rendered reconstruction providing an overview of the left anterior

descending coronary artery (LAD) showing signs of extensive atherosclerosis in the mid LAD

(arrow). (B) An enlargement of the mid LAD demonstrating presence of extensive calcifi cations. (C)

Multiplanar reconstruction of the LAD demonstrating the presence of diffuse atherosclerosis in the

mid LAD (arrow) with luminal narrowing, enlargement showing cross-sectional view of the LAD

with calcifi ed and non-calcifi ed elements. (D) CCA demonstrating no signs of signifi cant luminal

narrowing in the LAD. (E) IVUS cross-sectional image of the mid LAD confi rming the presence of

extensive atherosclerosis with calcifi cations (arrows) and a plaque burden of ≥40%.

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However, minimal lumen area on IVUS was not signifi cantly different between true positives and false positives (3.9 mm

(IQR 3.0 - 5.6 mm

) versus 4.1 mm

(IQR 3.6 - 7.6 mm

), p=0.136). More importantly, plaque burden on IVUS was not signifi cantly different between true and false positives (56% (IQR 50 - 62%) versus 56% (IQR 46 - 63%), p=0.484) implying that substantial atherosclerosis is present in lesions that are falsely classifi ed as positive for stenosis on CTA despite the absence of signifi cant luminal narrowing (Figure 2B). A case example of a patient with stenosis on CTA in the absence of signifi cant stenosis on CCA is provided in Figure 3.

DISCUSSION

The present study is the fi rst to perform a comprehensive evaluation of the diagnostic performance of CTA. We systematically investigated the diagnostic accuracy of CTA for the detection of signifi cant stenosis (with CCA as the reference standard) as well as for the detection of atherosclerosis (using IVUS as the reference standard) in a large patient population. In the current study, regarding the accuracy of CTA to detect signifi cant steno- sis, a negative predictive value of 100% and a diagnostic accuracy of 92% were observed on a patient level. Importantly, no patients with signifi cant stenosis were missed. Never- theless, nine patients (9% of the total population) were incorrectly classifi ed as having a signifi cant stenosis resulting in a limited positive predictive value of 81%. However, when the defi nition of disease was changed from signifi cant stenosis (gold standard CCA) to the presence of atherosclerosis (gold standard IVUS), the performance of CTA improved and an excellent diagnostic accuracy was observed. Further exploration of lesions incorrectly classifi ed as having signifi cant stenosis on CTA confi rmed the presence of substantial plaque burden in these segments. The fi ndings of the present study demonstrate that CTA may be superior in the evaluation of the presence or the absence of visually evi- dent atherosclerosis on IVUS when compared with the evaluation of signifi cant stenosis.

Accordingly, CTA may therefore perform better in the assessment of atherosclerosis rather than the evaluation of stenosis severity. Conceivably, precisely this information on athero- sclerosis, which cannot be derived from CCA, may become increasingly important in the defi nition and subsequent management of CAD.

The present observations regarding the diagnostic accuracy for detection of signifi cant

stenosis are in line with the previous literature using 64-row CTA.

Recently in a multicen-

tre trial, the diagnostic performance of 64-row CTA was investigated in 230 symptomatic

patients with suspected CAD, reporting a sensitivity and specifi city of 95% and 83% on

a patient basis, respectively.

However, while in this study the negative predictive value

(on a patient basis) was high (99%), a relatively low positive predictive value of 64% was

reported. Indeed, due to limitations in spatial resolution it has been established that CTA

cannot precisely grade the severity of stenosis and frequently overestimates the degree of

luminal narrowing. Similarly, in the present study, 17 segments were incorrectly identifi ed

as having signifi cant stenosis leading to a positive predictive value for detecting signifi cant

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stenosis of only 77% on segmental basis and 81% on patient basis. Therefore, while CTA remains an excellent tool for ruling out the presence of signifi cant stenosis, a substantial proportion of lesions are overestimated, thereby resulting in incorrect diagnosis.

Importantly, when changing the defi nition of CAD from the presence of signifi cant stenosis to the presence of atherosclerosis, the overestimated lesions were no longer false positive studies. Comparison with IVUS revealed that in all of these patients despite the absence of signifi cant luminal narrowing, substantial plaque burden was present.

Accordingly, CTA had excellent diagnostic accuracy for the detection of atherosclerosis when compared with IVUS. Importantly, no patients with visually evident atherosclerosis (as determined on IVUS) were missed nor was the presence of atherosclerosis incorrectly diagnosed. On a segmental and vessel level, only slightly lower values were observed.

Accurate assessment of atherosclerosis with CTA has previously been demonstrated in several investigations. When compared with histology, a good correlation for detecting and characterizing atherosclerotic plaque was reported.

In vivo, Leber et al observed a sensitivity and specifi city for 16-row CTA of respectively 85% and 92% to detect coronary lesions as determined on IVUS.

Evaluation of the characteristics of lesions missed on CTA revealed that particularly small plaques located in distal segments were not identifi ed. In contrast, larger and proximally located plaques, which may be considered more clinically relevant, were accurately detected.

Clinical implications

At present, CCA is the gold standard for detecting severely stenotic lesions and remains

the basis for referral for surgical and catheter-based revascularization. However, CCA has

a tendency to underestimate total atherosclerotic plaque burden (partly due to positive

remodeling) and more detailed characterization of atherosclerosis is not feasible at pres-

ent. Currently, the gold standard for assessing and quantifying coronary artery plaque

burden is IVUS. Nevertheless, the use of this invasive technique is restricted to patients

with a high likelihood of having signifi cant lesions requiring intervention. In contrast,

non-invasive CTA will typically be used in lower likelihood patients and thus to evaluate

the presence of CAD in more early stages. This technique has been proved very useful

in the clinical setting and particularly due to the high negative predictive value it can

accurately rule out the presence of signifi cant disease in the majority of patients with

a low to intermediate pre-test risk profi le. While the technique accurately rules out the

presence of signifi cant stenosis, the limited positive predictive value (potentially resulting

in unnecessary invasive procedures) has been a cause of concern. However in this regard,

two issues are important to acknowledge. First, as demonstrated in the current study,

coronary segments false positive for signifi cant stenosis may not necessarily be false

positive for atherosclerosis. Accordingly, these fi ndings may still be considered relevant

for risk stratifi cation and initiation of anti-atherosclerotic measures. Second, regardless

of the actual severity of the detected lesion, functional testing remains essential to

determine the haemodynamical consequences of the lesion.

The presence and extent

of ischaemia rather than an estimate of luminal narrowing should invariably serve as the

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102

basis for further referral for CCA and possible revascularization. Considering these issues, it is conceivable that the emphasis of CTA, which traditionally has been on the evaluation of signifi cant stenosis, may shift towards the evaluation of atherosclerosis.

As demonstrated in our systematic comparison of CTA with both CCA and IVUS, the diagnostic accuracy of CTA for detecting the presence of atherosclerosis was superior over the detection of signifi cant stenosis. In fact, the ability of CTA to accurately exclude the presence of atherosclerosis may be considered superior over other non-invasive tech- niques. Importantly, supporting data are emerging that patients without any evidence of atherosclerotic plaques on CTA have excellent prognosis that is maintained over a relatively long period of time.

In these patients, CTA may obviate the need for further testing and unnecessary aggressive therapy. In contrast, patients with atherosclerotic plaques on CTA have been shown to have worse outcome. These patients may thus be- nefi t from intensifi ed treatment, while further evaluation with functional testing remains essential to determine the need for revascularization. On the basis of these and the current observations, it is conceivable therefore that shifting the use of CTA from mere stenosis assessment towards evaluation of atherosclerosis may have several advantages for clinical management and may allow improved risk stratifi cation.

Limitations

In the current study, only patients with suffi cient CTA image quality for the evaluation of both the presence of signifi cant stenosis and atherosclerosis were included. In addition, a verifi cation bias could be present, as in a limited number of cases patients were referred for CCA on the basis of CTA fi ndings. Moreover, in the present study, no nitroglycerine was administered before the CT scan. Furthermore, concerns have been raised about CTA radiation dose, especially with respect to the long term effects. However, the recent intro- duction of single heart beat imaging (320-row CTA), dose modulation and particularly prospective triggering have drastically reduced patient radiation dose. Future research will most likely focus on further decreasing radiation exposure while maintaining good image quality.

Conclusion

The present study is the fi rst to perform a comprehensive evaluation of the diagnostic

accuracy of CTA for the detection of signifi cant stenosis and for the presence of athero-

sclerosis. In this regard, the diagnostic accuracy of CTA for the detection of the presence

of atherosclerosis was superior over the detection of signifi cant stenosis. Possibly, the

emphasis of CTA should shift towards the evaluation of atherosclerosis rather than mere

stenosis severity.

Chapt er 5

103

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